Anti-inflammatory properties of a platelet-activating factor acetylhydrolase

Tjoelker, Larry W.; Wilder, Cheryl; Eberhardt, Chris; Stafforinit, Diana M.; Dietsch, Gregory N.; Schimpf, Brian A.; Hooper, Shawn; Trong, Hai Le; Cousens, Lawrence S.; Zimmerman, Guy A.; Yamadat, Yoshiji; Mclntyre, Thomas M.; Prescott, Stephen M.; Gray, Patrick W.

doi:10.1038/374549a0

Cited by 496 publications

(391 citation statements)

References 26 publications

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“…Five ESTs derived from human tissue cDNA libraries displayed significant sequence homology with the plant sequence. The sequences of two of these (accession numbers H39628 and H44282) were used to generate PCR primers for screening a human macrophage cDNA plasmid library (26). A partial macrophage cDNA was used to screen a human heart muscle cDNA library for additional clones.…”

Section: Resultsmentioning

confidence: 99%

“…Based upon the EST sequences, two oligonucleotide primers (forward: 5Ј-GGGCCTCATCA-TGTACCTCGGGGGCG-3Ј; reverse: 5Ј-CTGCCCTCCCCCAGGTC-3Ј) were designed and used in a polymerase chain reaction (PCR) to obtain a fragment of the LPAAT homologue cDNA from a human macrophage cDNA library (26). The fragment was used to generate a radiolabeled probe by random priming (Random Primed Labeling Kit, Boehringer Mannheim) that was applied to both a human heart muscle cDNA library in Lambda Zap II and a genomic DNA library in Lambda Fix II (both from Stratagene, La Jolla, CA).…”

Section: Methodsmentioning

confidence: 99%

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Human Lysophosphatidic Acid Acyltransferase

Eberhardt

Gray

Tjoelker

1997

Journal of Biological Chemistry

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114

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Lysophosphatidic acid (1-acyl-sn-glycero-3-phosphate (LPA)) is a phospholipid with diverse biological activities. The mediator serves as an intermediate in membrane phospholipid metabolism but is also produced in acute settings by activated platelets. LPA is converted to phosphatidic acid, itself a lipid mediator, by an LPA acyltransferase (LPAAT). A human expressed sequence tag was identified by homology with a coconut LPAAT and used to isolate a full-length human cDNA from a heart muscle library. The predicted amino acid sequence bears 33% identity with a Caenorhabditis elegans LPAAT homologue and 23-28% identity with plant and prokaryotic LPAATs. Recombinant protein produced in COS 7 cells exhibited LPAAT activity with a preference for LPA as the acceptor phosphoglycerol and arachidonyl coenzyme A as the acyl donor. Northern blotting demonstrated that the mRNA is expressed in most human tissues including a panel of brain subregions; expression is highest in liver and pancreas and lowest in placenta. The human LPAAT gene is contained on six exons that map to chromosome 9, region q34.3.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Human Lysophosphatidic Acid Acyltransferase

Eberhardt

Gray

Tjoelker

1997

Journal of Biological Chemistry

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114

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“…There are at least two levels of control defined: the enzymatic cleavage of PAF and the down-regulation of PAFR. The inactivation of PAF by acetylhydrolase is well studied and may be an important step in limiting inflammatory responses (43). Relatively less is known about the regulation of PAFR.…”

Section: Discussionmentioning

confidence: 99%

Activation Via Multiple Signaling Pathways Induces Down-Regulation of Platelet-Activating Factor Receptors on Human B Lymphocytes

Zhuang

Bastien

Mazer

2000

The Journal of Immunology

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Platelet-activating factor receptor (PAFR) has been identified in B cell lines and primary human B cells, but the regulation of PAFR during B cell activation has not been completely elucidated. In the present study, we have investigated the effects of B cell activation on PAFR binding parameters, PAFR mRNA and PAF-triggered intracellular calcium mobilization. The human B lymphoid cell line LA350 was shown to exhibit high levels of PAFR (48,550 ± 4,310 sites/cell) as determined by radio-ligand binding assay with PAFR antagonist [3H]WEB2086. Treatment with phorbol 12,13-dibutyrate caused a biphasic reduction of PAFR binding. The early phase was inhibited by the protein kinase C inhibitor bisindolylmaleimide I (BIM), whereas the late phase was not blocked by BIM, protein tyrosine kinase inhibitor genistein, or the mitogen-activated protein kinase/extracellular signal-related kinase inhibitor PD98059. However, staurosporine, a broad-spectrum protein kinase inhibitor, completely inhibited the late phase down-regulation. Ionomycin also decreased [3H]WEB2086 binding sites, whereas the combination of PDB and ionomycin induced a greater reduction than either agent alone. Cross-linking of B cell receptor by anti-IgM Ab also induced down-regulation of PAFR, which was abolished by genistein or PD98059, but not by BIM or staurosporine. The decrease in surface PAFR number was closely paralleled by the reduction in PAFR mRNA both in LA350 cells and human tonsillar B cells, and was associated with decreased response to PAF indicated by decreased intracellular calcium mobilization. These data show that multiple signaling pathways are involved in down-regulating PAFR expression during B cell activation and development.

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“…PAF is then rapidly degraded to lyso-PAF by PAF acetylhydrolases (15). Alternatively, lyso-PAF is again transformed into PC by the action of lysophosphatidylcholine (LPC) acyltransferase (2.3.1.23) (16).A G protein-coupled PAF receptor was cloned in our laboratory (17), and PAF acetylhydrolases have been cloned and characterized by others (18,19). Lyso-PAF acetyltransferase was initially demonstrated and partially characterized by Wykle et al (14) in 1980.…”

mentioning

confidence: 99%

“…A G protein-coupled PAF receptor was cloned in our laboratory (17), and PAF acetylhydrolases have been cloned and characterized by others (18,19). Lyso-PAF acetyltransferase was initially demonstrated and partially characterized by Wykle et al (14) in 1980.…”

mentioning

confidence: 99%

A Single Enzyme Catalyzes Both Platelet-activating Factor Production and Membrane Biogenesis of Inflammatory Cells

Shindou¹,

Hishikawa²,

Nakanishi

et al. 2007

Journal of Biological Chemistry

223

239

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Platelet-activating factor (PAF) is a potent proinflammatory lipid mediator eliciting a variety of cellular functions. Lipid mediators, including PAF are produced from membrane phospholipids by enzymatic cascades. Although a G protein-coupled PAF receptor and degradation enzymes have been cloned and characterized, the PAF biosynthetic enzyme, aceyl-CoA:lyso-PAF acetyltransferase, has not been identified. Here, we cloned lyso-PAF acetyltransferase, which is critical in stimulusdependent formation of PAF. The enzyme is a 60-kDa microsomal protein with three putative membrane-spanning domains. The enzyme was induced by bacterial endotoxin (lipopolysaccharide), which was suppressed by dexamethasone treatment. Surprisingly, the enzyme catalyzed not only biosynthesis of PAF from lyso-PAF but also incorporation of arachidonoyl-CoA to produce PAF precursor membrane glycerophospholipids (lysophosphatidylcholine acyltransferase activity). Under resting conditions, the enzyme prefers arachidonoyl-CoA and contributes to membrane biogenesis. Upon acute inflammatory stimulation with lipopolysaccharide, the activated enzyme utilizes acetyl-CoA more efficiently and produces PAF. Thus, our findings provide a novel concept that a single enzyme catalyzes membrane biogenesis of inflammatory cells while producing a prophlogistic mediator in response to external stimuli.Platelet-activating factor (PAF 3 ; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a phospholipid mediator that activates a G protein-coupled receptor (1-3) and results in pleiotropic and potent biological effects, including platelet activation, airway constriction, and hypotension (1). PAF is synthesized in various cells and tissues via two distinct pathways, the de novo and remodeling pathways (2, 4, 5), and the latter is regulated by extracellular signals and plays a critical role in stimulus-coupled PAF biosynthesis (2, 4 -6). PAF synthesis induced by extracellular signals has been reported in murine peritoneal cells stimulated by calcium ionophore (7) or by PAF (8), in human eosinophils stimulated by fMet-Leu-Phe (9), in human neutrophils stimulated by acid stress (10), and in murine peritoneal macrophages stimulated by lipopolysaccharide (LPS) (11). In the remodeling pathway, the precursor of PAF, 1-Oalkyl-sn-glycero-3-phosphocholine (lyso-PAF), is synthesized from 1-O-alkyl-2-arachidonoyl-sn-glycero-3-phosphocholine (1-alkyl-phosphatidylcholine; PC) by the action of phospholipase A 2 (2, 4, 12, 13). Subsequently, lyso-PAF is converted to PAF by acetyl-CoA:lyso-PAF acetyltransferase (lyso-PAF acetyltransferase) (EC 2.3.1.67) (14). PAF is then rapidly degraded to lyso-PAF by PAF acetylhydrolases (15). Alternatively, lyso-PAF is again transformed into PC by the action of lysophosphatidylcholine (LPC) acyltransferase (2.3.1.23) (16).A G protein-coupled PAF receptor was cloned in our laboratory (17), and PAF acetylhydrolases have been cloned and characterized by others (18,19). Lyso-PAF acetyltransferase was initially demonstrated and partially characterized by ...

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Anti-inflammatory properties of a platelet-activating factor acetylhydrolase

Cited by 496 publications

References 26 publications

Human Lysophosphatidic Acid Acyltransferase

Human Lysophosphatidic Acid Acyltransferase

Activation Via Multiple Signaling Pathways Induces Down-Regulation of Platelet-Activating Factor Receptors on Human B Lymphocytes

A Single Enzyme Catalyzes Both Platelet-activating Factor Production and Membrane Biogenesis of Inflammatory Cells

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